Potassium channel inhibitors

ABSTRACT

Certain thiazolidinone and metathiazanone compounds, as described, are useful as potassium channel inhibitors and are especially useful for the treatment of cardiac arrhythmias and other diseases, conditions and disorders.

This application is a continuation of Ser. No. 09/307,708, filed May 1,1999 now U.S. Pat No. 6,174,908, which claimed the benefit under 35U.S.C. §119(e)(1) of prior filed provisional application No. 60/088,228filed Jun 5, 1998.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is broadly directed to a class of thiazolidinoneand metathiazanone compounds and their derivatives useful as potassiumchannel inhibitors.

2. Description of Related Art

Potassium channels are expressed in eukaryotic and procaryotic cells,and are elements in the control of electrical and nonelectrical cellularfunctions. Subclasses of these channels have been named based on aminoacid sequence and functional properties, and include for example voltagegated potassium channels (e.g., Kv1, Kv2, Kv3, Kv4). Subtypes withinthese subclasses have been characterized as to their putative function,pharmacology and distribution in cells and tissues (Chandy and Gutman,“Voltage-gated potassium channel genes” in Handbook of Receptors andChannels-Ligand and Voltage-gated Ion Channels, ed. R. A. North, 1995;Doupnik et al., Curr. Opin. Neurobiol. 5:268, 1995).

Inhibitors of potassium channels lead to a decrease in potassium ionmovement across cell membranes. Consequently, such inhibitors induceprolongation of the electrical action potential or membrane potentialdepolarization in cells containing the inhibited or blocked potassiumchannels. Prolonging of the electrical action potential is a preferredmechanism for treating certain diseases, e.g., cardiac arrhythmias(Colatsky et al., Circulation 82:2235, 1990). Membrane potentialdepolarization is a preferred mechanism for the treating of certainother diseases, such as those involving the immune system (Kaczorowskiand Koo, Perspectives in Drug Discovery and Design, 2:233, 1994).

Potassium channels which exhibit functional, pharmacological and tissuedistribution characteristics have been cloned. These cloned potassiumchannels are useful targets in assays for identifying candidatecompounds for the treatment of various disease states. For example, thedelayed rectifier voltage-gated potassium channel termed I_(kur) orI_(sus) which has been reported to contain the Kv1.5 α-subunit geneproduct is generally believed to be important in the repolarization ofthe human atrial action potential and thus is a candidate potassiumchannel target for the treatment of cardiac arrhythmias especially thoseoccurring in the atria (Wang et al., Circ. Res. 73:1061, 1993; Fedida etal., Circ. Res. 73:210, 1993; Wang et al., J. Pharmacol Exp. Ther.272:184, 1995; Amos et al., J. Physiol, 491:31, 1996).

The present invention is related to thiazolidinone and metathiazanonecompounds which have been found to be useful as inhibitors of potassiumchannel function. Such compounds have been found to be especially activeas inhibitors of voltage-gated potassium channels and may therefore beutilized for the treatment of diseases, conditions and disorders inwhich prolongation of cellular action potentials or the induction ofcell membrane depolarization would be beneficial. These disease states,conditions and disorders include, but are not limited to cardiacarrhythmias, cell proliferative disorders including cancer, disorders ofthe auditory system, central nervous system mediated motor dysfunctionand disorders of pulmonary, vascular and visceral smooth musclecontractility.

It is an object of the present invention, therefore, to provide a methodof treating diseases, conditions and disorders in mammals, includinghumans, which respond to the inhibition of potassium channel function,which method comprises administering to a mammal in need thereof certainthiazolidinone or metathiazanone compounds.

Another object of the invention is to provide certain thiazolidinone andmetathiazanone compounds which are useful for the treatment of suchdiseases, conditions and disorders in mammals, including humans.

DETAILED DESCRIPTION OF THE INVENTION

This invention describes certain thiazolidinone and metathiazanonecompounds and their utility as inhibitors of voltage-dependent potassiumchannel function, particularly potassium channels (i.e., I_(Kur), Kv1.5)that could serve as targets for the treatment of cardiac arrhythmiasespecially those occurring in the atria (e.g., atrial flutter and atrialfibrillation) (Wang et al., Circ. Res. 73:1061, 1993; Fedida et al.,Circ. Res. 73:210, 1993; Wang et al., J. Pharmacol. Exp. Ther. 272:184,1995), as well as the potassium channels that could serve as targets forthe treatment of immunologic diseases and conditions and disorders ofthe nervous system and the gastrointestinal system. Consequently, thepresent invention also provides a method for treating diseases,conditions and disorders which respond to the inhibition of potassiumchannel function such as cardiac arrhythmias and various immunologic,nervous and gatrointestinal diseases using certain thiazolidinone andmetathiazanone compounds.

The invention is particularly based on the discovery that thiazolidinoneand metathiazanone compounds of the following formula (I), andpharmaceutically acceptable salts, esters, amides, complexes, chelates,hydrates, stereoisomers, crystalline or amorphous forms, metabolites,metabolic precursors or prodrugs thereof, are inhibitors of potassiumchannel function. In particular, these thiazolidinone and metathiazanonecompounds have demonstrated activity against the human potassiumchannels/currents I_(Kur), Kv1.5. As a result, these compounds areuseful in the treatment inter alia, of cardiac arrhythmias and otherdiseases, conditions and disorders.

Thus, in a first aspect, the present invention concerns a method fortreating diseases, conditions and disorders which respond to theinhibition of potassium channel function by using a compound having theformula (I) and pharmaceutically acceptable salts, esters, amides,complexes, chelates, hydrates, stereoisomers, crystalline or amorphousforms, metabolites, metabolic precursors or prodrugs thereof:

wherein,

v is 0 or 1;

t is 0, 1, or 2;

X in an orientation R¹—X—, is selected from —(CR⁴ ₂)_(p)—; —(CR⁴₂)_(m)O(CR⁴ ₂)_(n)—; —(CR⁴ ₂)_(m)CH═CH(CR⁴ ₂)_(s)—;—(CR⁴ ₂)_(m)CH≡CH(CR⁴₂)_(s)—; —(CR⁴ ₂)_(m)—A—(CR⁴ ₂)_(m)—;

—(CR⁴ ₂)_(m)—NR⁴—(CR⁴ ₂)_(n)—;

 where p is an integer of 0 to 5, n is an integer of 2 to 4, m is aninteger of 0 to 4 and s is an integer of 1 to 4; A is selected from anoptionally substituted 3 to 7 membered carbocyclic ring and anoptionally substituted 5 to 7 membered heterocyclic ring; each R⁴ isindependently selected from H, a lower alkyl, an aryl and a heteroaryl;W is selected from O and NR⁵ where R⁵ is selected from H, lower alkyl,aryl, C≡N and NHR⁴;

R¹ is selected from H, an optionally substituted aryl and an optionallysubstituted heteroaryl;

Y, in an orientation R²—Y—, is selected from —(CR⁴ ₂)_(q)—; —(CR⁴₂)_(m)O(CR⁴ ₂)_(n)—; —(CR⁴ ₂)_(m)CH═CH(CR⁴ ₂)_(m)—; —(CR⁴₂)_(m)CH≡CH(CR⁴ ₂)_(m)—; —(CR⁴ ₂)_(m)—A—(CR⁴ ₂)_(m)— and a cycloalkyl,where q is an integer of 0 to 4 and m and n are as defined above;

R² is selected from H, an optionally substituted aryl and an optionallysubstituted heteroaryl; and

R³ is selected from H, optionally substituted lower alkyl, optionallysubstituted aryl, optionally substituted heteroaryl and —NR⁶R⁷, where R⁶is selected from H and optionally substituted lower alkyl; R⁷ is H,optionally substituted lower alkyl, optionally substituted aryl,—(SO₂)R⁸, —COR⁸ and —C(O)NH—R⁴, R⁸ is selected from optionallysubstituted lower alkyl, optionally substituted aryl and optionallysubstituted heteroaryl or R⁶ and R⁷ together with the nitrogen to whichthey are attached form a heteroaryl.

When v is 1, formula (I) relates to a class of metathiazanone compoundsof the following formula, with the various variables as defined above:

When v is 0, formula (I) relates to a class of thiazolidinone compoundsof the following formula, with the various variables as defined above:

In a preferred aspect, the present invention concerns a method fortreating diseases, conditions and disorders which respond to theinhibition of potassium channel function by using a compound having theformula (II) and pharmaceutically acceptable salts, esters, amides,complexes, chelates, hydrates, stereoisomers, crystalline or amorphousforms, metabolites, metabolic precursors or prodrugs thereof:

wherein,

v is 0, or 1;

t is 0, 1, or 2;

X, in an orientation R¹—X—, is selected from —(CR⁴ ₂)_(p)—; —(CR⁴₂)_(m)O(CR⁴ ₂)_(n)—; —(CR⁴ ₂)_(m)CH═CH(CR⁴ ₂)_(s)—; —(CR⁴₂)_(m)CH≡CH(CR⁴ ₂)_(s)—; and —(CR⁴ ₂)_(m)—A—(CR⁴ ₂)_(m)—; where p is aninteger of 0 to 5, n is an integer of 2 to 4, m is an integer of 0 to 4and s is an integer of 1 to 4; A is an optionally substituted 3 to 7membered carbocyclic ring; each R⁴ is independently selected from H, alower alkyl, an aryl and a heteroaryl;

R¹ is selected from an optionally substituted aryl and an optionallysubstituted heteroaryl;

Y, in an orientation R²—Y—, is selected from —(CR⁴ ₂)_(q)—; —(CR⁴₂)_(m)O(CR⁴ ₂)_(n)—; —(CR⁴ ₂)_(m)CH═CH(CR⁴ ₂)_(m)—; —(CR⁴₂)_(m)CH≡CH(CR⁴ ₂)_(m)—;—(CR⁴ ₂)_(m—A—(CR) ⁴ ₂)_(m)—and a cycloalkyl,where q is an integer of 0 to 4 and m and n are as defined above;

R² is selected from H, an optionally substituted aryl and an optionallysubstituted heteroaryl; and

R³ is selected from H, optionally substituted lower alkyl, optionallysubstituted aryl, optionally substituted heteroaryl and —NR⁶R⁷, where R⁶is selected from H and optionally substituted lower alkyl; R⁷ is Hoptionally substituted lower alkyl, optionally substituted aryl,—(SO₂)R⁸, —COR⁸ and —C(O)NH—R⁴, R⁸ is selected from optionallysubstituted lower alkyl, optionally substituted aryl and optionallysubstituted heteroaryl or R⁶ and R⁷ together with the nitrogen to whichthey are attached form a heteroaryl.

More preferred is a method for treating diseases, conditions anddisorders which respond to the inhibition of potassium channel functionby using a compound having the formula (III) and pharmaceuticallyacceptable salts, esters, amides, complexes, chelates, hydrates,stereoisomers, crystalline or amorphous forms, metabolites, metabolicprecursors or prodrugs thereof:

wherein,

v is 0, or 1

t is 0, 1,or 2;

X, in an orientation R¹—X—, is selected from —(CR⁴ ₂)_(p)—; —(CR⁴₂)_(m)CH═CH(CR⁴ ₂)_(s)—; —(CR⁴ ₂)_(m)CH≡CH(CR⁴ ₂)_(s)—; and —(CR⁴₂)_(m)—A—(CR⁴ ₂)_(m)—; where p is an integer of 0 to 5, n is an integerof 2 to 4, m is an integer of 0 to 4 and s is an integer of 1 to 3; A isan optionally substituted 3 to 7 membered carbocyclic ring; each R⁴ isindependently selected from H, a lower alkyl, an aryl and a heteroaryl;

R¹ is selected from an optionally substituted aryl and an optionallysubstituted heteroaryl;

R² is an optionally substituted phenyl; and

R³ is selected from H, optionally substituted lower alkyl, optionallysubstituted aryl, optionally substituted heteroaryl and —NR⁶R⁷, where R⁶is selected from H and optionally substituted lower alkyl; R⁷ is H,optionally substituted lower alkyl, optionally substituted aryl,—(SO₂)R⁸, —COR⁸ and —C(O)NH—R⁴, R⁸ is selected from optionallysubstituted lower alkyl, optionally substituted aryl and optionallysubstituted heteroaryl or R⁶ and R⁷ together with the nitrogen to whichthey are attached form a heteroaryl.

In yet another aspect, the present invention is directed to certaincompounds having the formula (IV) and pharmaceutically acceptable salts,esters, amides, complexes, chelates, hydrates, stereoisomers,crystalline or amorphous forms, metabolites, metabolic precursors orprodrugs thereof:

wherein,

v is 0, or 1;

t is 0, 1, or 2;

X in an orientation R¹—X—, is selected from —(CR⁴ ₂)_(p)—;—(CR⁴ ₂3)(CH₂)—; —(CR⁴ ₂)_(m)O(CR⁴ ₂)_(n)—; —(CR⁴ ₂)_(m)CH═CH(CR⁴ ₂)_(s)—;—(CR⁴ ₂)_(m)CH≡CH(CR⁴ ₂)_(s)—; —(CR⁴ ₂)_(m—A—(CR) ⁴ ₂)_(m)—;

—(CR⁴ ₂)_(m)—NR⁴—(CR⁴ ₂)_(n)—;

 where p is an integer of 3 to 5, n is an integer of 2 to 4, m is aninteger of 0 to 4 and s is an integer of 1 to 4; A is selected from anoptionally substituted 3 to 7 membered carbocyclic ring and anoptionally substituted 5 to 7 membered heterocyclic ring; each R⁴ isindependently selected from H, a lower alkyl, an aryl and a heteroaryl;W is selected from O and NR⁵; R⁵ is selected from H, lower alkyl, aryl,C≡N and NHR⁴;

R¹ is selected from H an optionally substituted aryl and an optionallysubstituted heteroaryl;

R² is selected from an optionally substituted aryl and an optionallysubstituted heteroaryl, with the provisos that (1) when X is —(CR⁴₂(CH₂)— and R⁴ is H then R¹ cannot be a monoalkylamino or dialkylaminosubstituted alkoxy substituted phenyl; (2) when X is —(CR⁴ ₂)_(p)—, R⁴is H and p is 3 to 4 then R¹ cannot be a monoalkylamino or dialkylaminosubstituted alkoxy substituted phenyl; (3) when X is —(CR⁴ ₂)(CH₂)— andR⁴ is H then R¹ cannot be p-nitrophenyl, p-aminophenyl,(3-methoxy-4-ethoxyphenyl), or H and (4) when X is —(CR⁴ ₂)(CH₂)— and R¹is not H, then R² cannot be pyridyl or indolyl.

In a preferred aspect, the present invention also concerns compoundshaving the formula (V) and pharmaceutically acceptable salts, esters,amides, complexes, chelates, hydrates, stereoisomers, crystalline oramorphous forms, metabolites, metabolic precursors or prodrugs thereof:

wherein,

v is 0, or 1;

t is 0, 1, or 2;

X in an orientation R¹—X—, is selected from —(CR⁴ ₂)_(p)—;—(CR⁴₂)(CH₂)—; —(CR⁴ ₂)_(m)O(CR⁴ ₂)_(n)—; —(CR⁴ ₂)_(m)CH═CH(CR⁴ ₂)_(s)—;—(CR⁴ ₂)_(m)CH≡CH(CR⁴ ₂)_(s)—; and —(CR⁴ ₂)_(m)—A—(CR⁴ ₂)_(m)—; where pis an integer of 3 to 5, n is an integer of 2 to 4, m is an integer of 0to 4 and s is an integer of 1 to 4; A is an optionally substituted 3 to7 membered carbocyclic ring; each R⁴ is independently selected from H, alower alkyl, an aryl and a heteroaryl;

R¹ is selected from an optionally substituted aryl and an optionallysubstituted heteroaryl; and

R² is selected from an optionally substituted aryl and an optionallysubstituted heteroaryl, with the provisos that (1) when X is —(CR⁴₂)(CH₂)— and R⁴ is H then R¹ cannot be a monoalkylamino or dialkylaminosubstituted alkoxy substituted phenyl; (2) when X is —(CR⁴ ₂)_(p)—, R⁴is H and p is 3 to 4 then R¹ cannot be a monoalkylamino or dialkylaminosubstituted alkoxy substituted phenyl; (3) when X is —(CR⁴ ₂)(CH₂)— andR⁴ is H then R¹ cannot be p-nitrophenyl, p-aminophenyl,(3-methoxy-4-ethoxyphenyl), or H and (4) when X is —(CR⁴ ₂)(CH₂)— and R¹is not H, then R² cannot be pyridyl or indolyl.

More preferred are compounds having the formula (VI) andpharmaceutically acceptable salts, esters, amides, complexes, chelates,hydrates, stereoisomers, crystalline or amorphous forms, metabolites,metabolic precursors or prodrugs thereof:

wherein,

v is 0, or 1;

t is 0, 1, or 2;

X, in an orientation R¹—X—, is selected from —(CR⁴ ₂)_(p)—;—(CR⁴₂)(CH₂)—; —(CR⁴ ₂)_(m)CH═CH(CR⁴ ₂)_(s)—; —(CR⁴ ₂)_(m)CH≡CH(CR⁴ ₂)_(s)—;and —(CR⁴ ₂)_(m)—A—(CR⁴ ₂)_(m)—; where p is an integer of 3 to 5, n isan integer of 2 to 4, m is an integer of 0 to 4 and s is an integer of 1to 3; A is an optionally substituted 3 to 7 membered carbocyclic ring;each R⁴ is independently selected from H, a lower alkyl, an aryl and aheteroaryl;

R¹ is selected from an optionally substituted aryl and an optionallysubstituted heteroaryl; and

R² is an optionally substituted phenyl, with the provisos that (1) whenX is —(CR⁴ ₂)(CH₂)— and R⁴ is H then R¹ cannot be a monoalkylamino ordialkylamino substituted alkoxy substituted phenyl; (2) when X is —(CR⁴₂)_(p)—, R⁴ is H and p is 3 to 4 then R¹ cannot be a monoalkylamino ordialkylamino substituted alkoxy substituted phenyl; (3) when X is —(CR⁴₂)(CH₂)— and R⁴ is H then R¹ cannot be p-nitrophenyl, p-aminophenyl,(3-methoxy-4-ethoxyphenyl), or H and (4) when X is —(CR⁴ ₂)(CH₂)— and R¹is not H, then R² cannot be pyridyl or indolyl.

Preferred R¹ substituents in formulae (I) through (VI) include phenyl;m- and p-methoxyphenyl; 3,4-methoxyphenyl; p-ethoxyphenyl;p-methylphenyl; p-ethylphenyl; 3,4-dimethylphenyl; 2,4-dichlorophenyl;p-chlorophenyl; p-bromophenyl; 3-bromo, 4-methoxyphenyl; indanyl andp-phenoxyphenyl. Preferred moieties for X in formulae (I) through (VI),in an orientation R¹—X—, include —CH₂CH₂—; —(CH₂)₃—; —(CH₂)₅—;—OCH₂CH₂—; —CHCH₂CH— (cyclopropyl); —CH₂C(O)—; —CH₂CH═CH— and —CH₂C≡C—.Preferred R² substituents in formulae (I) through (VI) include phenyl;m-methylphenyl; 3-methyl, 4-methoxyphenyl; 3,4-dimethylphenyl;p-dimethylaminophenyl; m-methoxyphenyl, p-methoxyphenyl; naphthyl;3,5-dimethylphenyl; p-(1-pyrrolidinyl)phenyl; 3,4-dichlorophenyl;benzodioxane; 3-bromo, 4-methoxyphenyl; 3,5-dimethoxylphenyl;1,3-benzodioxol-5-yl; 3-(1-methyl indolyl); 2-quinolyl; 2-(5-ethylthienyl); 2-(5-ethyl furyl); 2-(4,5-dimethyl furyl);3,4-dimethoxylphenyl; p-methylthiophenyl; indanyl; naphthyl;p-ethylphenyl; p-isopropylphenyl; 2,3-dimethyl, 4-methoxyphenyl;o-methoxyphenyl; 2,5-dimethyl, 4-methoxyphenyl; 3,4dichlorophenyl;o-chlorophenyl; m-bromophenyl and 3-methylthio, 4-cyanophenyl. Preferredmoieties for Y in formulae (I) and (II), in an orientation R²—Y—,include a simple covalent bond (i.e., —(CR⁴ ₂)_(q) with q=0),—CH(C₆H₅)—; —CH₂—; —CH₂CH₂— and —CH(CH₃)—. Finally, the method, compoundand compositions of the present invention are particularly directed tothose instances involving formulae (I) through (VI) where v is 0 and tis 0.

The term “alkyl” as used alone or in combination herein refers to astraight or branched chain saturated hydrocarbon group containing fromone to ten carbon atoms and the terms “C₁₋₆ alkyl” and “lower alkyl”refer to such groups containing from one to six carbon atoms, such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl and the like. The term “optionally substituted” when used inconnection with an alkyl substituent refers to the replacement of up totwo hydrogens, preferably on different carbon atoms with a radicalselected form the group of lower alkoxy, phenyl, cyano, halo,trifluoromethyl, nitro, hydroxyl, alkanoyl, amino, monoalkyl amino anddialkylamino.

The term “alkoxy” as used alone or in combination herein refers to astraight or branched chain alkyl group covalently bonded to the parentmolecule through an —O— linkage containing from one to ten carbon atomsand the terms. “C₁₋₆ alkoxy” and “lower alkoxy” refer to such groupscontaining from one to six carbon atoms, such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, t-butoxy and the like. The term “optionallysubstituted” when used in connection with an alkoxy substituent refersto the replacement of up to two hydrogens, preferably on differentcarbon atoms with a radical selected form the group of lower alkyl,phenyl, cyano, halo, trifluoromethyl, nitro, hydroxyl, alkanoyl, amino,monoalkyl amino and dialkylamino.

The term “alkoxyalkyl” refers to an alkyl group substituted with analkoxy group.

The term “haloalkyl” is a substituted alkyl, preferably a substitutedlower alkyl, substituted with one or more halogen atoms, and preferablyis a C₁ to C₄ alkyl substituted with one to three halogen atoms. Oneexample of a haloalkyl is trifluoromethyl.

The term “alkanoyl” as used alone or in combination herein refers to anacyl radical derived from an alkanecarboxylic acid, particularly a loweralkanecarboxylic acid, and includes such examples as acetyl, propionyl,butyryl, valeryl, and 4-methylvaleryl.

The term “aminocarbonyl” means an amino-substituted carbonyl (carbamoylor carboxamide) wherein the amino group can be a primary, secondary(mono-substituted amino) or tertiary amino (di-substituted amino) grouppreferably having as a substituent(s) a lower alkyl.

The term “carbocyclic ring” refers to stable, saturated or partiallyunsaturated monocyclic ring hydrocarbyls of 3 to 7 carbon atoms such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Theterm “optionally substituted” as it refers to “carbocyclic ring” hereinindicates that the carbocyclic ring may be substituted at one or moresubstitutable ring positions by one or more groups independentlyselected from alkyl (preferably lower alkyl), alkoxy (preferably loweralkoxy), nitro, monoalkylamino (preferably a lower alkylamino),dialkylamino (preferably a di[lower]alkylamino), cyano, halo, haloalkyl(preferably trifluoromethyl), alkanoyl, aminocarbonyl,monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl amido (preferablylower alkyl amido), alkoxyalkyl (preferably a lower alkoxy[lower]alkyl),alkoxycarbonyl (preferably a lower alkoxycarbonyl), alkylcarbonyloxy(preferably a lower alkylcarbonyloxy) and aryl (preferably phenyl), saidaryl being optionally substituted by halo, lower alkyl and lower alkoxygroups.

The term “carbocycloalkyl” refers to stable, saturated or partiallyunsaturated monocyclic, bridged monocyclic, bicyclic, and spiro ringhydrocarbyls of 3 to 15 carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, bicyclohexyl, bicyclooctyl,bicyclononyl, spirononyl and spirodecyl. The term “optionallysubstituted” as it refers to “carbocycloalkyl” herein indicates that thecarbocycloalkyl group may be substituted at one or more substitutablering positions by one or more groups independently selected from alkyl(preferably lower alkyl), alkoxy (preferably lower alkoxy), nitro,monoalkylamino (preferably a lower alkylamino), dialkylamino (preferablya di[lower]alkylamino), cyano, halo, haloalkyl (preferablytrifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl,dialkylaminocarbonyl, alkyl amido (preferably lower alkyl amido),alkoxyalkyl (preferably a lower alkoxy[lower]alkyl), alkoxycarbonyl(preferably a lower alkoxycarbonyl), alkylcarbonyloxy preferably a loweralkylcarbonyloxy) and aryl (preferably phenyl), said aryl beingoptionally substituted by halo, lower alkyl and lower alkoxy groups.

The term “heterocyclic ring” as used herein refers to a stable,saturated, or partially unsaturated monocyclic ring system containing 5to 7 ring members of carbon atoms and other atoms selected fromnitrogen, sulfur and/or oxygen. Preferably, a heterocyclyl is a 5 or6-membered monocyclic ring and contains one, two, or three heteroatomsselected from nitrogen, oxygen and/or sulfur. The term “optionallysubstituted” as it refers to “heterocyclic ring” herein indicates thatthe heterocyclic ring may be substituted at one or more substitutablering positions by one or more groups independently selected from alkyl(preferably lower alkyl), alkoxy (preferably lower alkoxy), nitro,monoalkylamino (preferably a lower alkylamino), dialkylamino (preferablya di[lower]alkylamino), cyano, halo, haloalkyl (preferablytrifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl,dialkylaminocarbonyl, alkyl amido (preferably lower alkyl amido),alkoxyalkyl (preferably a lower alkoxy[lower]alkyl), alkoxycarbonyl(preferably a lower alkoxycarbonyl), alkylcarbonyloxy (preferably alower alkylcarbonyloxy) and aryl (preferably phenyl), said aryl beingoptionally substituted by halo, lower alkyl and lower alkoxy groups.Examples of such heterocyclic rings are isoxazolyl, imidazolinyl,thiazolinyl, imidazolidinyl, pyrrolyl, pyrrolinyl, pyranyl, pyrazinyl,piperidyl, morpholinyl and triazolyl. The heterocyclic ring may beattached to the parent structure through a carbon atom or through anyheteroatom of the heterocyclyl that results in a stable structure.

The term “heterocyclyl” as used herein refers to a stable, saturated, orpartially unsaturated, monocyclic, bridged monocyclic, bicyclic, andspiro ring system containing carbon atoms and other atoms selected fromnitrogen, sulfur and/or oxygen. Preferably, a heterocyclyl is a 5 or6-membered monocyclic ring or an 8-11 membered bicyclic ring whichconsists of carbon atoms and contains one, two, or three heteroatomsselected from nitrogen, oxygen and/or sulfur. The term “optionallysubstituted” as it refers to “heterocyclyl” herein indicates that theheterocyclyl group may be substituted at one or more substitutable ringpositions by one or more groups independently selected from alkyl(preferably lower alkyl), alkoxy (preferably lower alkoxy), nitro,monoalkylamino (preferably a lower alkylamino), dialkylamino (preferablya di[lower]alkylamino), cyano, halo, haloalkyl (preferablytrifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl,dialkylaminocarbonyl, alkyl amido (preferably lower alkyl amido),alkoxyalkyl (preferably a lower alkoxy[lower]alkyl), alkoxycarbonyl(preferably a lower alkoxycarbonyl), alkylcarbonyloxy (preferably alower alkylcarbonyloxy) and aryl (preferably phenyl), said aryl beingoptionally substituted by halo, lower alkyl and lower alkoxy groups.Examples of such heterocyclyl groups are isoxazolyl, imidazolinyl,thiazolinyl, imidazolidinyl, pyrrolyl, pyrrolinyl, pyranyl, pyrazinyl,piperidyl, morpholinyl and triazolyl. The heterocyclyl group may beattached to the parent structure through a carbon atom or through anyheteroatom of the heterocyclyl that results in a stable structure.

The term “heteroaryl” as used herein refers to a stable, aromaticmonocyclic or bicyclic ring system containing carbon atoms and otheratoms selected from nitrogen, sulfur and/or oxygen. Preferably, aheteroaryl is a 5 or 6-membered monocyclic ring (optionally benzofused)or an 8-11 membered bicyclic ring which consists of carbon atoms andcontains one, two, or three heteroatoms selected from nitrogen, oxygenand/or sulfur. The term “optionally substituted” as it refers to“heteroaryl” herein indicates that the heteroaryl group may besubstituted at one or more substitutable ring positions by one or moregroups independently selected from alkyl (preferably lower alkyl),alkoxy (preferably lower alkoxy), nitro, monoalkylamino (preferably alower alkylamino), dialkylamino (preferably a di[lower]alkylamino,cyano, halo, haloalkyl (preferably trifluoromethyl), alkanoyl,aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl amido(preferably lower alkyl amido), alkoxyalkyl (preferably a loweralkoxy[lower]alkyl), alkoxycarbonyl (preferably a lower alkoxycarbonyl),alkylcarbonyloxy (preferably a lower alkylcarbonyloxy) and aryl(preferably phenyl), said aryl being optionally substituted by halo,lower alkyl and lower alkoxy groups. Examples of such heteroaryl groupsare isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridyl, furyl,pyrimidinyl, pyrazolyl, pyridazinyl, furazanyl and thienyl. Theheteroaryl group may be attached to the parent structure through acarbon atom or through any heteroatom of the heteroaryl that results ina stable structure.

The specific chemical nature of the optionally substituted heteroarylgroups for the terminal moieties R¹ and R² in the prior identifiedpotassium channel inhibitor compounds is not narrowly critical and, asnoted above, a wide variety of substituent groups are contemplated.Preferably, the substituents for the heteroaryl groups are selected suchthat the total number of carbon and hetero atoms comprising thesubstituted heteroaryls is no more than about 20.

The terms “halo” and “halogen” as used herein to identify substituentmoieties, represent fluorine, chlorine, bromine or iodine, preferablychlorine or fluorine.

The term “aryl” when used alone or in combination refers to anunsubstituted or optionally substituted monocyclic or bicyclic aromatichydrocarbon ring system. Preferred are optionally substituted phenyl ornaphthyl groups. The aryl group may optionally be substituted at one ormore substitutable ring positions by one or more groups independentlyselected from optionally substituted alkyl (preferably an optionallysubstituted lower alkyl), optionally substituted alkoxy (preferably anoptionally substituted lower alkoxy), nitro, monoalkylamino (preferablya lower alkylamino), dialkylamino (preferably a di[lower]alkylamino),cyano, halo, haloalkyl (preferably trifluoromethyl), alkanoyl,aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl amido(preferably lower alkyl amido), alkoxyalkyl (preferably a loweralkoxy[lower]alkyl), alkoxycarbonyl (preferably a lower alkoxycarbonyl),alkylcarbonyloxy (preferably a lower alkylcarbonyloxy) and aryl(preferably phenyl), said aryl being optionally substituted by halo,lower alkyl and lower alkoxy groups. Preferably, the aryl group isphenyl optionally substituted with up to four and usually with one ortwo groups, preferably selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, as well ascyano, trifluoromethyl and halo. Two alkyl or two alkoxy substituents ona substituted phenyl may form a closed ring structure between the metaand para positions on the phenyl, thus forming an indanyl, benzodioxane,benzopyran and the like groups.

The term “aralkyl” alone or in combination refers to an alkyl radical asdefined above in which one hydrogen atom is replaced by an aryl radicalas defined above, and includes benzyl, and 2-phenylethyl.

The term “alkoxycarbonyl” alone or in combination means a radical of theformula —C(O)—alkoxy, in which alkoxy is as defined above.

The term “alkylcarbonyloxy” alone or in combination means a radical ofthe formula —O—C(O)-alkyl, in which alkyl is as defined above.

The term “alkenyl” means a two to seven carbon, straight or branchedhydrocarbon containing one or more double bonds, preferably one or twodouble bonds. Examples of alkenyl include ethenylene, propenylene,1,3-butadienyl, and 1,3,5-hexatrienyl.

Unless otherwise defined, the term “optionally substituted” as usedherein, refers to the substitution of a ring system at one or morepositions with one or more groups selected from: C₁₋₆ alkyl, C₁₋₆alkoxy, an optionally substituted phenyl, cyano, halo, trifluoromethyl,C₁₋₈ alkoxycarbonyl, C₁₋₆ alkyl carbonyloxy, mono- & bis-(C₁₋₆alkyl)-carboxamide, C₁₋₆ alkyl amido, nitro, and mono- & bis-(C₁₋₆alkyl)-amino.

The term “treating” as used herein, describes the management and care ofa patient afflicted with a condition, disease or disorder for which theadministration of a compound in accordance with the present inventionalters the action or activity of a potassium channel to prevent theonset of symptoms or complications associated with the condition,disease or disorder, to alleviate the symptoms or complications causedby the condition, disease or disorder, or to eliminate the condition,disease or disorder altogether.

Thiazolidinone and metathiazanone compounds of the previous formulaeuseful as potassium channel inhibitors in accordance with the presentinvention can be prepared in accordance with the following generalprocedure:

A mixture of an amine (1 equivalent), an aldehyde (2 equivalents), and amercaptoacid (3 equivalents) in benzene or toluene is heated to atemperature in the range of 80° C. to 100°. In some cases an aminehydrochloride can be used. In those instances, about 1-1.5 equivalentsof NEt₃ also are added. After 2-24 hr, the reaction mixture is allowedto cool to room temperature and the solvent can be removed under reducedpressure. The crude product is dissolved in EtOAc and washed withsaturated NaHCO₃, 1N HCl, and saturated NaCl. The organic layer is dried(Na₂SO₄), filtered and concentrated. Purification by columnchromatography on silica gel gives the desired thiazolidinone ormetathiazanone product. Oxidation of a thiazolidinone or ametathiazanone to the corresponding sulfoxide or sulfone is readilyaccomplished by treatment with meta-chloroperbenzoic acid at 0° C.

It is recognized that there is at least one chiral center in thecompounds used within the scope of the present invention and thus suchcompounds will exist as various stereoisomeric forms. Applicants intendto include all the various stereoisomers within the scope of theinvention. Though the compounds may be prepared as racemates and canconveniently be used as such, individual enantiomers also can beisolated or preferentially synthesized by known techniques if desired.Such racemates and individual enantiomers and mixtures thereof areintended to be included within the scope of the present invention.

The present invention also encompasses the pharmaceutically acceptablesalts, esters, amides, complexes, chelates, hydrates, crystalline oramorphous forms, metabolites, metabolic precursors or prodrugs of thecompounds of formulae (I), (II), (III), (V), (V) and (VI).Pharmaceutically acceptable esters and amides can be prepared byreacting, respectively, a hydroxy or amino functional group with apharmaceutically acceptable organic acid, such as identified below. Aprodrug is a drug which has been chemically modified and may bebiologically inactive at its site of action, but which is degraded ormodified by one or more enzymatic or other in vivo processes to theparent bioactive form. Generally, a prodrug has a differentpharmakokinetic profile than the parent drug such that, for example, itis more easily absorbed across the mucosal epithelium, it has bettersalt formation or solubility and/or it has better systemic stability(e.g., an increased plasma half-life).

Those skilled in the art recognize that chemical modifications of aparent drug to yield a prodrug include: (1) terminal ester or amidederivatives which are susceptible to being cleaved by esterases orlipases; (2) terminal peptides which may be recognized by specific ornonspecific proteases; or (3) a derivative that causes the prodrug toaccumulate at a site of action through membrane selection, andcombinations of the above techniques. Conventional procedures for theselection and preparation of prodrug derivatives are described in H,Bundgaard, Design of Prodrugs, (1985). Those skilled in the art arewell-versed in the preparation of prodrugs and are well-aware of itsmeaning.

As will be recognized by those skilled in the art, certain compoundsused in accordance with the present invention can be used in their neatform or in the form of pharmaceutically-acceptable salts derived frominorganic or organic acids. Examples of acids which may be employed toform pharmaceutically acceptable acid addition salts of compounds of thepresent invention include such inorganic acids as hydrochloric acid,sulphuric acid and phosphoric acid and such organic acids as oxalicacid, maleic acid, succinic acid and citric acid. These salts thusinclude, but are not limited to, the following: acetate, adipate,alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsulfonate, digluconate,cyclopentanepropionate, dodecylsulfate, ethanesulfonate,glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide hydroiodide,2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate,nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate,persulfate, 3-phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate.

Also, any basic nitrogen-containing groups in compounds of the inventioncan be quaternized with such agents as lower alkyl halides, such asmethyl, ethyl, propyl, and butyl chlorides, bromides and iodides;dialkyl sulfates, like dimethyl, diethyl, dibutyl and diamyl sulfates,long chain halides such as decyl, lauryl, myristyl and stearylchlorides, omides and iodides, aralkyl halides like benzyl and phenethylbromides and others. Water or oil soluble or dispersible products arethereby generally obtained.

The pharmaceutically acceptable salts of compounds used in accordancewith the present invention also can exist as various solvates, such aswith water, methanol, ethanol, dimethylformamide, ethyl acetate and thelike. Mixtures of such solvates also can be prepared. Such solvates arewithin the scope of the present invention.

The pharmacological profile of the potassium channel inhibitory activityof thiazolidinone and metathiazanone compounds falling within theteachings of the present invention can be readily assessed by thoseskilled in the art using routine experimentation, such as the proceduresand techniques illustrated in the examples which follow. Assays forassessing the activity of particular compounds may employ cells stablytransfected to express a specific potassium channel, as well as nativemammalian cells. In particular, cells stably transfected to express aspecific potassium channel, which have been treated with a voltagedependent fluorescent dye, such as bis-1,3-dibutylbarbituricacid)trimethine oxonol, can be used to gauge the inhibitory activity ofpotassium channel inhibitor compounds, possibly in comparison to knowninhibitors. Alternatively, such cells can be primed with a detectiblespecies, such as ⁸⁶Rb, and then challenged with a particular compound,under conditions otherwise suitable for activating the potassiumchannel, to assess the potassium inhibitory activity of the compound.The potassium channel inhibitory activity of a compound also can bedetermined using isolated mammalian cells and the whole cellconfiguration of the known patch clamp technique (Hamill et al.,Pflugers Archiv 391:85, 1981). These and other known techniques can bereadily employed by those skilled in the art to assess the activitylevel of the potassium channel inhibitor compounds contemplated by thepresent invention.

Thiazolidinone and metathiazanone compounds suitable for use within thescope of the present invention may be administered by a variety ofroutes including orally, parenterally, sublingually, intranasally, byinhalation spray, rectally, or topically in dosage unit formulationscontaining conventional nontoxic pharmaceutically acceptable carriers,adjuvants, and vehicles as desired. The term parenteral as used hereinincludes subcutaneous injections, intravenous, intramuscular,intracardiac injection, or infusion techniques. Topical administrationmay also involve the use of transdermal administration such astransdermal patches or iontophoresis devices.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,2-propanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring andperfuming agents.

Thiazolidinone and metathiazanone compounds contemplated for use withinthe scope of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed asmono- or multi-lamellar hydrated liquid crystals that are dispersed inan aqueous medium. Any non-toxic physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natural and synthetic. Methodsto form liposomes are known in the art. See, for example, Prescott, Ed.,Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.(1976), p. 33, et seq.

To select preferred compounds from less preferred compounds, one uses byexample the in vitro assays detailed under the sub-heading BioAssayshereafter. Typically, a preferred compound will produce half maximalblocking activity at a concentration ranging from about 10 nM to about 1μM in the in vitro assays described. One of ordinary skill willrecognize that the final and optimum dose and regimen will be determinedempirically for any given drug.

Total daily dose administered to a host in single or divided doses maybe an amount, for example, from 0.001 to 100 mg of active ingredient perkg body weight on a daily basis and more usually 0.01 to 10 mg/kg/day.Dosage unit compositions may contain such amounts of submultiplesthereof to make up the daily dose. It is anticipated that atherapeutically effective serum concentration of active ingredient willbe 10 nM to 10 μM (5 ng/ml to 5 μg/ml).

The amount of active ingredient that may be combined with carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, and diet of the patient, the time ofadministration, the route of administration, the rate of excretion,whether a drug combination is used, and the severity of the particulardisease.

The present invention is explained in greater detail in the Exampleswhich follow. These examples are intended as illustrative of theinvention, and are not to be taken as limiting thereof. Unless otherwiseindicated, all references to parts and percentages are based on weightand all temperatures are expressed in degrees Celsius. The scope of theinvention is not construed as merely consisting of the followingexamples.

EXAMPLES

Compound Preparation

All solvents and reagents were purchased from commercial suppliers andwere used without further purification. Analytical thin layerchromatography was performed on Whatman Inc. 60 silica gel plates (0.25mm thickness). Compounds were visualized under UV lamp or by developingwith KMnO₄/KOH, Flash chromatography was done using silica gel fromSelectro Scientific (particle size 32-63). ¹H NMR and ¹³C NMR spectrawere recorded at 300 MHz and 75.5 MHz, respectively.

Preparation 1

A mixture of m-anisaldehyde (0.74 ml; 6.1 mmol), mercaptoacetic acid(0.64 ml; 9.2 mmol), and 4-methoxyphenethylamine (0.46 g; 3.1 mmol) inbenzene (10 ml) was heated at 80° C. for 2.5 h. The reaction mixture wasallowed to cool to room temperature and the solvent was removed underreduced pressure. The residue was diluted with EtOAc (30 ml) and theorganic phase was washed with saturated NaHCO₃ (50 ml), 1 N HCl (50 ml)and saturated NaCl (50 ml), dried (Na₂SO₄), filtered and concentrated.Column chromatography on silica gel provided the product (Entry 1 ofTable 1) as a colorless oil (0.87 g; 83%). R_(f) (silica gel): 0.30 (70%hexane: 30% EtOAc); ¹H NMR (300 MHz, CDCl₃) 7.28 (t, J=7.8 Hz, 1H), 7.02(d, J=8.7 Hz, 2H), 6.89-6.73 (m, 5 H), 5.28 (s, 1H), 3.91-3.84 (m, 1H),3.79 (s, 3H), 3.28 (s, 3H), 3.78 (d, J=15.0 Hz, 1H), 3.66 (d, J=15.0 Hz,1H), 2.92-2.76 (m, 2H), 2.68-2.59 (m, 1H); ¹³C NMR (75.5 MHz, CDCl₃)171.5, 160.3, 158.5, 141.0, 130.5, 130.2, 129.8 (two carbons), 119.4,114.7, 114.1 (two carbons), 112.6, 63.9, 55.3, 55.2, 44.7, 32.8, 32.3.

Preparation 2

The procedure as described for Preparation 1 was repeated usingp-anisaldehyde, mercaptoacetic acid and 2-(p-tolyl)ethylamine asstarting materials. Yield (Entry 2 of Table 1): 56%. R_(f) (silica gel):0.44 (70% hexane: 30% EtOAc); ¹H NMR (300 MHz, CDCl₃) 7.15 (d, J=8.7 Hz,1H), 7.08 (d, J=7.8 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.88 (d, J 8.7 Hz,1H), 5.31 (s, 1H), 3.85-3.80 (m, 1H), 3.81 (s, 3H), 3.77 (d, J=1.5 and15.6 Hz, 1H), 3.67 (d, J=15.6 Hz, 1H), 2.91-2.76 (m, 2H), 2.66-2.56 (m,1H), 2.31 (s, 3H).

Preparation 3

The procedure as described for Preparation 1 was repeated using4-(1-pyrrolidino)benzaldehyde, mercaptoacetic acid, and4-methoxyphenethylamine as starting materials. Yield (Entry 3 of Table1): 86%. R_(f) (silica gel): 0.38 (70% hexane; 30% EtOAc); ¹H NMR (300MHz, CDCl₃) 7.08 (d, J=8.7 Hz, 1H), 7.02 (d, J=8.7 Hz, 1H), 6.81 (d,J=8.7 Hz, 1H), 6.51 (d, J=8.7 Hz, 1H), 5.31 (s, 1H), 3.82-3.75 (m, 1H),3.77 (s, 3H), 3.75 (dd, J=1.8 and 15.3 Hz, 1H) 3.65 (d, J=15.3 Hz, 1H),3.28 (t, J=6.6 Hz, 4H), 2.94-2.74 (m, 2H), 2.63-2.54 (m, 1H ), 2.06-1.92(m, 4H); ¹³C NMR (75.5 MHz, CDCl₃) 171.1, 158.4, 148.6, 130.8 , 129.8(two carbons), 128.7 (two carbons), 124.6, 114.0 (two carbons), 111.7(two carbons), 64.3, 55.2, 47.5 two carbons), 44.3, 33.1, 32.3, 25.4(two carbons).

Preparation 4

The procedure as described for Preparation 1 was repeated using1,4-dioxan-6-carboxyaldehyde, mercaptoacetic acid, and4-methoxyphenethylamine as starting materials. Yield (Entry 4 of Table1): 98%. R_(f) (silica gel): 0.26 (70% hexane: 30% EtOAc); ¹H NMR (300MHz, CDCl₃) 7.02 (d, J=8.7 Hz, 2H), 6.84-6.80 (m, 3H), 6.73 (d, J=2.1Hz, 1H), 6.67 (dd, J=2.1 and 8.4 Hz, 1H), 5.22 (d, J=1.2 Hz, 1H), 4.24(s, 3H), 3.87-3.80 (m, 1H), 3.78 (s, 1H), 3.74 (dd, J=1.5 Hz and 15.3Hz, 1H), 3.63 (d, J=15.3 Hz, 1H), 2.91-2.74 (m, 2H), 2.68-2.57 (m, 1H);¹³C NMR (75.5 MHz, CDCl₃) 171.1, 158.5, 144.4, 144.0, 132.5, 130.6,129.8 (two carbons), 120.3, 117.7, 116.1, 114.1 (two carbons), 64.3 (twocarbons), 63.6, 55.2, 44.5, 32.8, 32.3.

Preparation 5

The procedure as described for Preparation 1 was repeated using3,4-dimethoxybenzaldehyde, mercaptoacetic acid, and4-methoxyphenethylamine as starting materials. Yield (Entry 5 of Table1): 16%. R_(f) (silica gel): 0.20 (70% hexane: 30% EtOAc); ¹H NMR (300MHz, CDCl₃) 7.00 (d, J=8.7 Hz, 2H), 6.82-6.72 (m, 5H), 5.29 (s, 1H ),3.88 (s, 3H), 3.85 (s, 3H), 3.80-3.78 (m, 1H ), 3.77 (s, 3H), 3.74 (dd,J=1.8 and 15.3 Hz, 1H), 3.66 (d, J=15.3 Hz, 1H), 2.91-2.74 (m, 2H),2.66-2.56 (m, 1H); ¹³C NMR (75.5 MHz, CDCl₃) 171.2, 158.5, 150.0, 149.8,131.3, 130.6, 129.8 (two carbons), 120.2, 114.1 (two carbons), 110.9,109.9, 64.1, 56.0, 55.9, 55.2, 44.5, 32.9, 32.3.

Preparation 6

The procedure as described for Preparation 1 was repeated usingbenzaldehyde, mercaptoacetic acid, and 4-methoxyphenethylamine asstarting materials. Yield (Entry 31 of Table 1): 99% R_(f) (silica gel):0.26 (80% hexane: 20% EtOAc); ¹H NMR (300 MHz, CDCl₃) 7.37-7.35 (m, 3H),7.23-7.20 (m, 2H), 7.01 (d, J=8.7 Hz, 2H), 6.95 (d, J=8.7 Hz, 2H), 5.32(s, 1H), 3.88-3.82 (m, 1H), 3.77 (s, 3H), 3.77 (d, J=15.3 Hz, 1H), 3.66(d, J=15.3 Hz, 1H), 2.90-2.75 (m, 2H), 2.65-2.56 (m, 1H); ¹³C NMR (75.5MHz, CDCl₃) 171.3, 158.5, 139.5, 130.5, 129.8 (two carbons), 129.3,129.1 (two carbons), 127.3 (two carbons), 114.1 (two carbons), 64.0,55.2, 44.7, 32.8, 32.3.

Preparation 7

The procedure as described for Preparation 1 was repeated usingcyclohexane carboxyaldehyde, mercapotacetic acid, and4-methoxyphenethylamine as starting materials. Yield (Entry 32 of Table1): 98% R_(f) (silica gel): 0.45 (80% hexane: 20% EtOAc); ¹H NMR (300MHz, CDCl₃) 7.12 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 4.41 (s,1H), 3.95-3.86 (m, 1H), 3.76 (s, 3H), 3.48 (d, J=15.6 Hz, 1H), 3.56 (d,J=15.6 Hz, 1H), 3.13-3.04 (m, 1H), 2.89-2.71 (m, 2H), 1.85-1.65 (m, 4H),1.39-1.10 (m, 7H); ¹³C NMR (75.5 MHz, CDCl₃) 171.5, 158.5, 130.5, 129.7(two carbons), 114.1 (two carbons), 67.2, 55.2, 44.6, 41.0, 32.4 (twocarbons), 29.1, 26.0 (two carbons), 25.3, 24.0.

Preparation 8

The procedure as described for Preparation 1 was repeated using3,4-dimethylbenzaldehyde, mercaptoacetic acid, and4-methoxyphenethylamine as starting materials. Yield (Entry 52 of Table1): 95%. R_(f) (silica gel): 0.48 (70% hexane: 30% EtOAc); ¹H NMR (300MHz, CDCl₃) 7.12 (d, J=7.5 Hz, 1H), 7.03 (d, J=8.7 Hz, 2H), 6.97 (s,1H), 6.94 (d, J=8.7 Hz, 1H), 5.29 (d, J=1.2 Hz, 1H), 3.91-3.83 (m, 1H),3.78 (s, 3H), 3.77 (dd, J=1.8 and 15.3 Hz, 1H), 3.66 (d, J=15.3 Hz, 1H),2.91-2.75 (m, 2H), 2.68-2.59 (s, 1H), 2.26 (s, 6H); ¹³C NMR (75.5 MHz,CDCl₃)171.3, 158.5, 137.9, 137.5, 136.8, 130.6, 130.2, 129.8 (twocarbons), 128.2, 124.7, 114.1 (two carbons), 63.8, 55.2, 44.5, 32.8,32.3, 1.7, 19.5.

Preparation 9

A mixture of, 3,4-dimethylbenzaldehyde (0.190 g; 1.42 mmol),mercaptoacetic acid (0.14 ml; 2.0 ml), 2-(4-methoxyphenoxy)ethylaminehydrochloride (0.136 g; 0.668 mmol), and NEt₃ (0.11 ml; 0.79 mmol) inbenzene (6 ml) was heated at 80° C. for 6 h. The reaction mixture wasallowed to cool to room temperature and the solvent was removed underreduced pressure. The residue was diluted with EtOAc (20 ml) and theorganic phase was washed with saturated NaHCO₃ (20 ml), 1 N HCl (20 ml)and saturated NaCl (30 ml), dried (Na₂SO₄), filtered and concentrated.Column chromatography on silica gel provided the product (Entry 53 ofTable 1): as a colorless oil (0.229 g; 96%). R_(f) (silica gel): 0.56(60% hexane: 40% EtOAc); ¹H NMR (300 MHz, CDCl₃) 7.14 (d, J=7.2 Hz, 1H),7.07 (s, 1H), 7.06 (d, J=7.2 Hz, 1H), 6.84-6.76 (m, 4H), 5.84 (d J=0.9Hz, 1H), 4.14-4.06 (m, 1H), 3.98-3.88 (m, 2H), 3.80 (dd, J=1.8 and 15.6Hz, 1H), 3.76 (s, 3H), 3.70 (d, J=15.6 Hz, 1H), 3.15-3.05 (m, 1H), 2.26(s, 6H); ¹³C NMR (75.5 MHz, CDCl₃) 171.6, 154.3, 152.5, 137.9, 137.5,136.8, 130.3, 128.5, 124.9, 115.4 (two carbons), 114.8 (two carbons),66.3, 64.5, 55.7, 42.3, 32.7, 19.7, 19.4.

Preparation 10

The procedure as described for Preparation 9 was repeated using3,4-dimethylbenzaldehyde, mercaptoacetic acid, and 4-nitrophenethylaminehydrochloride as starting materials. Yield (Entry 65 of Table 1): 78%R_(f) (silica gel): 0.31 (70% hexane: 30% EtOAc); ¹H NMR (300 MHz,CDCl₃) 8.12 (d, J=8.7 Hz, 2H), 7.25 (, J=8.7 Hz, 2H), 7.13 (d, J=7.5 Hz,1H), 7.00 (s, 1H), 6.97 (d, J=7.5 Hz, 1H), 5.37 (d, J=1.2 Hz, 1H),3.89-3.80 (m, 1H), 3.79 (dd, J=1.2 and 15.6 Hz, 1H), 3.65 (d, J=15.6 Hz,1H), 3.06-2.89 (m, 2H), 2.81-2.72 (m, 1H), 2.26 (s, 6H); ¹³C NMR (75.5MHz, CDCl₃) 171.5, 147.0, 146.2, 138.3, 137.8, 136.4, 130.4, 129.7, (twocarbons), 128.2, 124.6, 123.8 (two carbons), 63.8, 43.8, 33.1, 32.7,19.7, 19.4.

Preparation 11

The procedure as described for Preparation 9 was repeated using3,4-dimethylbenzaldehyde, mercaptoacetic acid, 2-aminoacetophenonehydrochloride as starting materials. Yield (Entry 78 of Table 1): 44%R_(f) (silica gel): 0.64 (60% hexane: 40% EtOAc); ¹H NMR (300 MHz,CDCl₃) 7.84 (d J=7.5 Hz, 2H), 7.56 (t, J=7.2 Hz, 1H), 7.421 (t, J=7.5Hz, 2H), 7.12-7.03 (m, 3H), 5.86 (s, 1H), 5.20 (d, J=17.7 Hz, 1H),3.95-3.78 (m, 3H), 2.24 (s, 6H); ¹³C NMR (75.5 MHz, CDCl₃) 193.0, 172.4,138.3, 137.7, 135.5, 134.8, 133.9, 130.4, 128.82 (two carbons), 128.77,128.0 (two carbons), 125.2, 63.8, 48.3, 32.8, 19.7, 19.4.

Preparation 12

The procedure as described for Preparation 9 was repeated using3,4-dimethylbenzaldehyde, mercaptoacetic acid, and 3-phenyl-allylaminehydrochloride as starting materials. Yield (Entry 81 of Table 1): 34%R_(f) (silica gel): 0.49 (70% hexane: 30% EtOAc); ¹H NMR(300 MHz, CDCl₃)7.31-7.25 (m, 5H ), 7.15 (d, J=7.5 Hz, 1H), 7.07 (s, 1H), 7.02 (d, J=7.5Hz, 1H), 6.29 (d, J=15.9 Hz, 1H), 6.01 (ddd, J=5.1, 8.1, and 15.9 Hz,1H), 5.60 (d, J=1.8 Hz, 1H), 4.55 (ddd, J=1.8, 5.1, and 15.0 Hz, 1H),3.87 (dd, J=1.8 and 15.6 Hz, 1H), 3.73 (d, J=15.6 Hz, 1H), 3.35 (dd,J=8.1 and 15.0 Hz, 1H), 2.65 (s, 6H); ¹³C NMR (75.5 MHz, CDCl₃) 171.2,138.0, 137.6, 136.7, 136.3, 134.4, 130.3, 128.67 (two carbons), 128.30,128.0, 126.5 (two carbons), 124.69, 122.5, 63.1, 44.7, 33.0, 19.7, 19.4.

Preparation 13

The procedure as described for Preparation 9 was repeated using3,4-dimethylbenzaldehyde, mercaptoacetic acid, and3-phenylpropargylamine hydrochloride as starting materials. Yield (Entry82 of Table 1): 48% R_(f) (silica gel): 0.60 (70% hexane: 30% EtOAc); ¹HNMR (300 MHz, CDCl₃) 7.41-7.26 (m, 5H), 7.18-7.10 (m, 3H), 5.85 (d,J=1.8 Hz, 1H), 4.84 (d, J=17.4 Hz, 1H), 3.86 (dd, J=1.8 and 15.3 Hz,1H), 3.80 (d, J=15.3 Hz, 1H ), 3.54 (d, J=17.4 Hz, 1H), 2.27 (s, 6H);¹³C NMR (75.5 MHz, CDCl₃) 170.9, 139.2, 137.6, 135.9, 131.9, (twocarbons), 130.3, 128.7, 128.6, 128.4 (two carbons), 125.0, 122.4, 84.6,82.2, 62.9, 33.1, 32.9, 19.7, 19.5.

Using the principles and techniques of Preparations 1 through 13, andappropriate starting materials, which will be well-understood by thoseskilled in the art, a variety of other compounds falling within thescope of the present invention can be synthesized. In this regard,thiazolidinone compounds (compounds of formula (I) with v=0 and t=0)listed in the following Table 1 can be synthesized.

TABLE 1

Entry R¹—X— R²—Y— R³—  1 2-(4-methoxyphenethyl) 3-methoxyphenyl H  22-(4-methylphenethyl) 4-methoxyphenyl H  3 2-(4-methoxyphenethyl)4-pyrrolidinylphenyl H  4 2-(4-methoxyphenethyl) 4-benzodioxanyl H  52-(4-methoxyphenethyl) 3,4-dimethoxyphenyl H  6 2-(4-methoxyphenethyl)4-benzodioxolanyl H  7 2-(4-methoxyphenethyl) 3-methyl-4-methoxyphenyl H 8 2-(3-methoxyphenethyl) 4-benzodioxolanyl H  9 2-phenethyl3-methoxyphenyl H 10 2-(4-methoxyphenethyl) 4-ethylphenyl H 112-(4-methoxyphenethyl) 4-isopropoxyphenyl H 12 2-(4-methoxyphenethyl)4-methylthiophenyl H 13 2-(4-chlorophenethyl) 4-methoxyphenyl H 142-(4-methoxyphenethyl) 4-isopropylphenyl H 15 2-(4-methoxyphenethyl)4-benzoxyphenyl H 16 2-(3-methoxyphenethyl) 4-(N-acetyl)aminophenyl H 172-(4-methoxyphenethyl) 4-dimethylaminophenyl H 18 2-(4-ethylphenethyl)3-methoxyphenyl H 19 2-(4-phenoxyphenethyl) 2-methoxyphenyl H 202-(3,4-dimethoxyphenethyl) 4-ethylphenyl H 21 2-(4-methoxyphenethyl)3,4-dichlorophenyl H 22 2-(3,4-dimethoxyphenethyl) 4-dimethyiaminophenylH 23 2-(4-methoxyphenethyl) 3,4-difluorophenyl H 242-(3-bromo-4-methoxyphenethyl) 3-methoxyphenyl H 252-(2,4-dichlorophenethyl) 3-methoxyphenyl H 26 2-(4-methoxyphenethyl)3-benzodioxolanyl H 27 2-(4-methoxyphenethyl)2,3-dimethyl-4-methoxyphenyl H 28 2-(4-methoxyphenethyl) B-naphthyl H 292-(4-methoxyphenethyl) 2-thiophenyl H 30 2-(4-methoxyphenethyl)3-quinolinyl H 31 2-(4-methoxyphenethyl) phenyl H 322-(4-methoxyphenethyl) cyclohexyl H 33 2-(4-methoxyphenethyl) benzyl H34 2-(4-methoxyphenethyl) 3,5-dimethoxyphenyl H 35 3-phenpropyl4-dimethylaminophenyl H 36 4-methoxybenzyl 3-methoxyphenyl H 373-phenpropyl 4-ethylphenyl H 38 4-phenbutyl 2-methoxyphenyl H 39 n-hexyl4-dimethylaminophenyl H 40 4-methoxybenzyl 2-chlorophenyl H 412-(4-methoxyphenethyl) 3-methoxyphenyl Me 42 2-(4-methoxyphenethyl)4-ethylphenyl Me 43 2-(4-chlorophenethyl) 4-ethylphenyl Me 442-(4-methoxyphenethyl) 3-methyl-4-methoxyphenyl Me 452-(4-methoxyphenethyl) 4-benzodioxanyl Me 46 2-(4-bromophenethyl)4-methoxyphenyl H 47 2-(4-ethylphenethyl) 3-methylphenyl H 482-(-4-ethoxyphenethyl) 4-benzodioxolanyl H 49 2-phenethyl3-methyl-4-methoxyphenyl H 50 4-methoxybenzyl 3-methyl-4-methyoxyphenylH 51 2-phenoxyethyl phenyl H 52 2-(4-methoxyphenethyl)3,4-dimethylphenyl H 53 2-(4-methoxyphenoxyethyl) 3,4-dimethylphenyl H54 2-(3-methoxyphenethyl) 4-benzodioxanyl H 55 2-(3-methoxyphenethyl)2,4-dichlorophenyl H 56 n-pentyl 3-methoxyphenyl H 57 benzyl3,4-dimethylphenyl H 58 2-(3-methoxyphenethyl) 4-benzodioxanyl H 592-(3-methoxyphenethyl) 4-benzodioxolanyl H 60 4-phenbutyl3,4-dimethylphenyl H 61 2-(3-methoxyphenethyl) 3,4-dichlorophenyl H 622-(3-methoxyphenethyl) 3-methylphenyl H 63 2-(3-methoxyphenethyl)3-bromo-4-methoxyphenyl H 64 2-(3-methoxyphenethyl) β-naphthyl H 652-(4-nitrophenethyl) 3,4-dimethylphenyl H 66 2-(3-methoxyphenethyl)2,3-dimethyl-4-methoxyphenyl H 67 2-(4-methoxyphenethyl)5-ethyl-2-thiophenyl H 68 2-(3-methoxyphenethyl) 3-benzodioxolanyl H 692-phenoxyethyl 4-benzodioxolanyl H 70 2-phenoxyethyl 3,4-dimethylphenylH 71 2-phenoxyethyl 4-ethylphenyl H 72 2-(4-methylphenethyl)4-benzodioxolanyl H 73 2-(4-methylphenethyl) 3,4-dimethylphenyl H 742-(4-methylphenethyl) 4-ethylphenyl H 75 2-phenoxyethyl5-ethyl-2-thiophenyl H 76 2-phenoxyethyl 5-methyl-2-thiophenyl H 77n-hexyl 3-methoxyphenyl H 78

3,4-dimethylphenyl H 79

4-benzodioxolanyl H 80

3-methoxyphenyl H 81

3,4-dimethylphenyl H 82

3,4-dimethylphenyl H 83

4-ethylphenyl H 84

4-benzodioxolanyl H 85

3-methyl-4-methoxyphenyl H 86 2-(3-methoxyphenethyl) 2,4-dichlorophenylH

Preparation 14

The procedure as described for Preparation 1 of Table 1 was repeatedusing 3,4-dimethylbenzaldehyde, 3-mercaptopropionic acid, and4-methoxyphenethylamine as starting materials and toluene as thesolvent. Yield of desired compound (Entry 2 of Table 2, below): 44%R_(f) (silica gel): 0.35 (60% hexane; 40% EtOAc): ¹H MMR (300 MHZ,CDCl₃) 7.09 (d, J=8.4 Hz, 3H), 6.93-6.81 (m, 4H), 5.14, (s, 1H),4.31-4.23 (m, 1H), 3.78 (s, 3H), 2.91-2.68 (m, 6H), 2.60-2.54 (m, 1H),2.24 (s, 6H)); ¹³C NMR (75.5 MHz, CDCl₃) 169.45, 158.4, 137.1, 136.8,131.16, 130.0 (two carbons), 129.8, 127.9, 124.0, 114.0 (two carbons),62.6, 55.2, 50.1, 34.7, 32.9, 21.8, 19.8, 19.3.

Preparation 15

The procedure as described for Preparation 1 of Table 1 was repeatedusing 3,4-dimethylbenzaldehyde, 3-mercaptopropionic acid, and2-phenoxylethylamine as starting materials. Yield of desired compound(Entry 12 of Table 2): 49% R_(f) (silica gel): 0.43 (60% hexane; 40%EtOAc): ¹H NMR (300 MHz, CDCl₃) 7.27 (t, J=7.5 Hz, 2H), 7.14 (d, J=7.8Hz, 1H), 7.03-6.93 (m, 3H), 6.88 (d, J=7.8 Hz, 2H), 5.83 (s, 1H),4.39-4.24 (m, 2H), 4.14-4.05 (m, 1H), 3.16-3.07 (m, 1H), 2.88-2.77 (m,3H), 2.67-2.59 (m, 1H), 2.27 (s, 6H); ¹³C NMR (75.5 MHz, CDCl₃) 169.9,158.6, 137.2, 136.8, 129.9, 129.6 (three carbons), 127.9, 124.1, 121.1,114.6 (two carbons), 66.3, 63.6, 47.3, 34.6, 21.8, 19.8, 19.3.

Preparation 16

The procedure as described for Preparation 1 of Table 1 was repeatedusing piperonal, 3-mercaptoproprionic acid, and 4-methoxyphenethylamineas starting materials and toulene as the solvent. Yield of desiredcompound (Entry 18 of Table 2): 15% R_(f) (silica gel): 0.42 (50%hexane; 50% EtOAc); ¹H NMR (300 MHz, CDCl₃) 7.09 (d, J=8.4 Hz, 2H), 6.82(d, J=8.4 Hz, 2H), 6.74 (d, J=7.8 Hz, 1H), 6.66 (d, J=1.8 Hz, 1H), 6.59(dd, J=1.8 and 7.8 Hz, 1H), 5.96 (s, 2H), 5.08 (s, 1H), 4.30-4.21 (m,1H), 3.78 (s, 3H), 2.89-2.59 (m, 7H); ¹³C NMR (75.5 MHz, CDCl₃) 169.3,158.4, 148.3, 147.7, 133.2, 131.1, 129.9 (two carbons), 120.0, 114.0(two carbons), 107.9, 107.2, 101.5, 62.7, 55.2, 50.0, 34.6, 32.9, 21.9.

Using the principles and techniques of Preparations 14 through 16, andappropriate starting materials, which will be well-understood by thoseskilled in the art, a variety of other compounds falling within thescope of the present invention can be synthesized. In this regard,metathiazanone compounds (compounds of formula (I) with v=1 and t=0)listed in the following Table 2 can be synthesized.

TABLE 2

Entry R¹—X— R²—Y— R³ R⁴  1 2-(4-methylphenethyl) 4-benzodioxanyl NHMe H 2 2-(4-methoxyphenethyl) 3,4-dimethylphenyl H H  3 2-phenethyl4-benzodioxanyl H methyl  4 2-(4-chlorophenethyl) phenyl H H  52-(4-ethylphenethyl) 4-benzodioxanyl NHSO₂Me H  62-(2,4-dichlorophenethyl) 3,4-dimethylphenyl H methyl  7 3-phenpropyl3,4-dimethylphenyl H H  8 4-methoxybenzyl 3,4-dimethylphenyl NHCOPh H  94-phenbutyl 3,4-dimethylphenyl H H 10 2-(4-bromophenethyl)4-benzodioxolanyl H H 11 2-(3-methoxyphenethyl) 3,4-dichlorophenyl Hmethyl 12 2-phenoxyethyl 3,4-dimethylphenyl H H 132-(3-methoxyphenethyl) 3-methoxyphenyl NHMe H 14 4-methoxybenzyl3,4-dimethylphenyl H H 15 2-(3-methoxyphenethyl)2,3-dimethyl-4-methoxyphenyl H H 16 2-(4-methoxyphenethyl)3,4-dichlorophenyl H H 17 3-phenpropyl 4-benzodioxolanyl H methyl 182-(4-methoxyphenethyl) 4-benzodioxolanyl H H 19 2-(4-methoxyphenethyl)3-methyl-4-methoxyphenyl NHSO₂Ph H 20 2-(4-methoxyphenethyl)3-methoxyphenyl H methyl 21 2-(4-methoxyphenethyl) 4-ethylphenyl NHBn H22 2-(4-chlorophenethyl) 4-methoxyphenyl H H 23 2-(4-chlorophenethyl)4-dimethylaminophenyl H H 24 2-phenethyl 3,4-dimethylphenyl H H 252-phenethyl 3-methoxyphenyl H H

EXAMPLE BioAssays

⁸⁶Rb Efflux Assays

Cells stably transfected with cDNA for human Kv1.5 (in pcDNA3 vector)were grown as confluent monolayers in 96 well tissue culture plates inMEM alpha with 10% heat inactivated fetal bovine serum and 400 μg/mlG418. Cells were incubated overnight in growth media containing 1 μCi/ml⁸⁶Rb to permit intracellular uptake of the isotope. At the end of theincubation period, the ⁸⁶Rb solution is aspirated and the cells washedthree times with Earls Balanced Salt Solution (EBSS) which contains (inmM) 132 NaCl, 5.4 KCl, 1.8 CaCl₂, 0.8 mM MgCl₂ 10 mM HEPES and 5 mMglucose. The cells were then preincubated for 10 minutes at roomtemperature in 100 μl/well of EBSS or EBSS containing test compounds. Atthe end of this period the wells were aspirated and to each well is thenadded 100 μl of a modified EBSS solution containing 70 mM KCl (NaClreplaced by KCl) and the compound to be tested. The high KClconcentration is utilized to depolarize the cells to membrane potentialsthat will activate Kv1.5 channels. After a 1 minute incubation in 70 mMKCl EBSS plus test compound, the solution is removed and placed into theappropriate well of a 96 well counting plate for analysis. Finally 100μl of 0.1% sodium dodecyl sulfate in EBSS is added to each well to lysethe cells. The lysate is taken for analysis to determine final cellcontent of ⁸⁶Rb. Samples were counted in a Wallac Microbeta liquidscintillation counter by Cerenkov emission. Efflux is expressed as apercentage of the initial cell content of ⁸⁶Rb.

The testing results of selective compounds from Tables 1 and 2 usingthis assay are reported in Table 3 (flux) as the potency for inhibitionof ⁸⁶Rb efflux through Kv1.5 potassium channels expressed in CHO cellsby compounds of the invention.

Electrophysiological Studies

Electrophysiological recordings of potassium currents in Chinese hamsterovary cells stably expressing the gene construct for the Kv1.5 potassiumchannel subunit were performed using the whole cell configuration of thepatch clamp technique (Hamill et al., Pflugers Archiv 391:85, 1981).Cell lines expressing Kv1.5 were prepared using standard techniquesknown to those skilled in the art. Cells were plated on glass coverslipsat a density of 2×10⁴ cells/coverslip and used within 24-48 hours.Solutions used for electrophysiological recordings were as follows.Extracellular bathing solutions contained (in mM) 132 NaCl, 5.4 KCl, 1.8CaCl₂, 0.8 MgCl₂, 10 HEPES, 5 glucose at pH 7.3. Electrode pipettesolutions for measuring Kv1.5 contain (in mM) 100 KF, 40 KCl, 5 NaCl, 2MgCl₂, 5 mM EGTA, 10 mM HEPES and 5 glucose at pH 7.4, 295 mOsm. Thecoverslips were placed in a small chamber (volume ˜200 μl) on themechanical stage of an inverted microscope and perfumed (2 ml/min) withextracellular recording solution. Drug application is achieved via aseries of narrow-bore glass capillary tubes (inner diameter ˜100 μm)positioned approximately 200 μm from the cell.

The testing results of selective compounds from Tables 1 and 2 usingthis assay are reported in Table 3 (EP) as the potency for inhibition ofKv1.5 potassium currents by compounds of the invention.

TABLE 3 IC₅₀ (μM) IC₅₀ (μM) Entry Table (EP) (flux) 1 1 0.6 3.9 5 1 6.029.6 8 1 1.2  9.9 23 1 ND 14.5 36 1 4.7 30.0 45 1 0.6 ND 52 1 0.2  0.960 1 0.3  6.9 67 1 0.7  1.3 77 1 1.6 10.5 82 1 ND  4.7 2 2 0.3  1.5 18 21.0  1.5

The principles, preferred embodiments and modes of operation of thepresent invention have been described in the foregoing specification.The invention which is intended to be protected herein, however, is notto be construed as limited to the particular forms disclosed, since theyare to be regarded as illustrative rather than restrictive. Variationsand changes may be made by those skilled in the art without departingfrom the spirit of the invention. Those skilled in the art willrecognize variations in the processes as described above and willrecognize appropriate modifications based on the above disclosure formaking and using the compounds of the invention.

In the forgoing specification, the following abbreviations are used:

Designation Reagent or Fragment UV ultra-violet KMnO₄ potassiumpermanganate KOH potassium hydroxide NMR nuclear magnetic resonance Hzhertz MHz megahertz EtOAc ethyl acetate NaHCO₃ sodium bicarbonate HClhydrochloric acid NaCl sodium chloride Na₂SO₄ sodium sulfate R_(f)retention factor CDCl₃ chloroform-d NEt₃ triethylamine Bn benzyl Memethyl Ph phenyl

We claim:
 1. A compound having the following formula or apharmaceutically acceptable salt, ester, amide, or stereoisomer thereof:

wherein, v is 1 t is 0, 1, or 2; X, in an orientation R¹—X—, is selectedfrom —(CR⁴ ₂)_(p)—; —(CR⁴ ₂)(CH₂)—; —(CR⁴ ₂)_(m)O(CR⁴ ₂)_(n)—; —(CR⁴₂)_(m)CH═CH(CR⁴ ₂)_(s)—; —(CR⁴ ₂)_(m)CH ≡CH(CR⁴ ₂)_(s)—; —(CR⁴₂)_(m)—A—(CR⁴ ₂)_(m)—;

—(CR⁴ ₂)_(m)—NR⁴—(CR⁴ ₂)_(n)—;

 where p is an integer of 3 to 5, n is an integer of 2 to 4, m is aninteger of 0 to 4 and s is an integer of 1 to 4; A is selected from anoptionally substituted 3 to 7 membered carbocyclic ring and anoptionally substituted 5 to 7 membered heterocyclic ring; each R⁴ isindependently selected from H, a lower alkyl, an aryl and a heteroaryl;W is selected from O and NR⁵; R⁵ is selected from H, lower alkyl, aryl,C≡N and NHR⁴; R¹ is selected from an optionally substituted aryl and anoptionally substituted heteroaryl; R² is selected from an optionallysubstituted aryl and an optionally substituted heteroaryl, with theprovisos that (1) when X is —(CR⁴ ₂)(CH₂)— and R⁴ is H then R¹ cannot bea monoalkylamino or dialkylamino substituted alkoxy substituted phenyl;(2) when X is —(CR⁴ ₂)_(p)—, R⁴ is H and p is 3 to 4 then R¹ cannot be amonoalkylamino or dialkylamino substituted alkoxy substituted phenyl;(3) when X is —(CR⁴ ₂)(CH₂)— and R⁴ is H then R¹ cannot bep-nitrophenyl, p-aminophenyl, or (3methoxy-4-ethoxyphenyl) and (4) whenX is —(CR⁴ ₂)(CH₂)—, then R² cannot be pyridyl or indolyl.
 2. Thecompound of claim 1 wherein t is
 0. 3. A compound having the followingformula or a pharmaceutically acceptable salt, ester, amide, orstereoisomer thereof:

wherein, v is 1; t is 0, 1, or 2; X, in an orientation R¹—X—, isselected from —(CR⁴ ₂)_(p)—; —(CR⁴ ₂)(CH₂)—; —(CR⁴ ₂)_(m)O(CR⁴ ₂)_(n)—;—(CR⁴ ₂)_(m)CH═CH(CR⁴ ₂)_(s)—; —(CR⁴ ₂)_(m)CH≡CH(CR⁴ ₂)_(s)—; and —(CR⁴₂)_(m)—A—(CR⁴ ₂)_(m)—; where p is an integer of 3 to 5, n is an integerof 2 to 4, m is an integer of 0 to 4 and s is an integer of 1 to 4; A isan optionally substituted 3 to 7 membered carbocyclic ring; each R⁴ isindependently selected from H, a lower alkyl, an aryl and a heteroaryl;R¹ is selected from an optionally substituted aryl and an optionallysubstituted heteroaryl; and R² is selected from an optionallysubstituted aryl and an optionally substituted heteroaryl, with theprovisos that (1) when X is —(CR⁴ ₂)(CH₂)— and R⁴ is H then R¹ cannot bea monoalkylamino or dialkylamino substituted alkoxy substituted phenyl;(2) when X is —(CR⁴ ₂)_(p)—, R⁴ is H and p is 3 to 4 then R¹ cannot be amonoalkylamino or dialkylamino substituted alkoxy substituted phenyl;(3) when X is —(CR⁴ ₂)(CH₂)— and R⁴ is H then R¹ cannot bep-nitrophenyl, p-aminophenyl, or (3-methoxy-4-ethoxyphenyl) and (4) whenX is —(CR⁴ ₂)(CH₂)—, then R² cannot be pyridyl or indolyl.
 4. Thecompound of claim 3 wherein t is
 0. 5. A compound having the followingformula or a pharmaceutically acceptable salt, ester, amide, orstereoisomer thereof:

wherein, v is 1; t is 0, 1, or 2; X, in an orientation R¹—X—, isselected from —(CR⁴ ₂)_(p)—; —(CR⁴ ₂)(CH₂)—; —(CR⁴ ₂)_(m)CH═CH(CR⁴₂)_(s)—; —(CR⁴ ₂)_(m)CH≡CH(CR⁴ ₂)_(s)—; and —(CR⁴ ₂)_(m)—A—(CR⁴ ₂)_(m)—;where p is an integer of 3 to 5, n is an integer of 2 to 4, m is aninteger of 0 to 4 and s is an integer of 1 to 3; A is an optionallysubstituted 3 to 7 membered carbocyclic ring; each R⁴ is independentlyselected from H, a lower alkyl, an aryl and a heteroaryl; R¹ is selectedfrom an optionally substituted aryl and an optionally substitutedheteroaryl; and R² is an optionally substituted phenyl, with theprovisos that (1) when X is —(CR⁴ ₂)(CH₂)— and R⁴ is H then R¹ cannot bea monoalkylamino or dialkylamino substituted alkoxy substituted phenyl;(2) when X is —(CR⁴ ₂)_(p)—, R⁴ is H and p is 3 to 4 then R¹ cannot be amonoalkylamino or dialkylamino substituted alkoxy substituted phenyl;(3) when X is —(CR⁴ ₂)(CH₂)— and R⁴ is H then R¹ cannot bep-nitrophenyl, p-aminophenyl, or (3-methoxy-4-ethoxyphenyl) and (4) whenX is —(CR⁴ ₂)(CH₂)—, then R² cannot be pyridyl or indolyl.
 6. Thecompound of claim 5 wherein t is
 0. 7. A pharmaceutical compositioncomprising a compound of claim 1 or a pharmaceutically acceptable salt,ester, amide, or stereoisomer thereof; and a pharmaceutically acceptablediluent or carrier.
 8. A pharmaceutical composition comprising acompound of claim 3 or a pharmaceutically acceptable salt, ester, amide,or stereoisomer thereof and a pharmaceutically acceptable diluent orcarrier.
 9. A pharmaceutical composition comprising a compound of claim5 or a pharmaceutically acceptable salt, ester, amide, or stereoisomerthereof and a pharmaceutically acceptable diluent or carrier.
 10. Amethod for inhibiting potassium transport across cellular membranespossessing potassium channels comprising exposing a cell membranepossessing said channels to the presence of a compound of claim 10 or apharmaceutically acceptable salt, ester, amide, or stereoisomer thereof.11. The method of claim 10 wherein the potassium channel is a voltagegated potassium channel.
 12. The method of claim 12 wherein thepotassium channel is a potassium channel responsible for cardiac IKurpotassium current.
 13. The method of claim 13 wherein said disease,condition or disorder is cardiac arrhythmia.
 14. A method for treating adisease, condition, or disorder which responds to the inhibition ofpotassium channel function by administering to a patient in needthereof, a pharmaceutically effective amount of a compound having thefollowing formula, or a pharmaceutically acceptable salt, ester, amide,or stereoisomer thereof:

wherein, v is 1; t is 0, 1, or 2; X, in an orientation R¹—X—, isselected from —(CR⁴ ₂)_(p)—; —(CR⁴ ₂)_(m)O(CR⁴ ₂)_(n)—; —(CR⁴₂)_(m)CH═CH(CR⁴ ₂)_(s)—; —(CR⁴ ₂)_(m)CH≡CH(CR⁴ ₂)_(s)—; —(CR⁴₂)_(m)—A—(CR⁴ ₂)_(m)—;

—(CR⁴ ₂)_(m)—NR⁴—(CR⁴ ₂)_(n)—;

 where p is an integer of 0 to 5, n is an integer of 2 to 4, m is aninteger of 0 to 4 and s is an integer of 1 to 4; A is selected from anoptionally substituted 3 to 7 membered carbocyclic ring and anoptionally substituted 5 to 7 membered heterocyclic ring; each R⁴ isindependently selected from H, a lower alkyl, an aryl and a heteroaryl;W is selected from O and NR⁵ where R⁵ is selected from H, lower alkyl,aryl, C≡N and NHR⁴; R¹ is selected from an optionally substituted aryland an optionally substituted heteroaryl; Y, in an orientation R²—Y—, isselected from —(CR⁴ ₂)_(q)—; —(CR⁴ ₂)_(m)O(CR⁴ ₂)_(n)—; —(CR⁴₂)_(m)CH═CH(CR⁴ ₂)_(m)—; —(CR⁴ ₂)_(m)CH≡CH(CR⁴ ₂)_(m)—; —(CR⁴₂)_(m)—A—(CR⁴ ₂)_(m)— and a cycloalkyl, where q is an integer of 0 to 4and m and n are as defined above; R² is selected from H, an optionallysubstituted aryl and an optionally substituted heteroaryl; and R³ isselected from H, optionally substituted lower alkyl, optionallysubstituted aryl, optionally substituted heteroaryl and —NR⁶R⁷, where R⁶is selected from H and optionally substituted lower alkyl; R⁷ is H,optionally substituted lower alkyl, optionally substituted aryl,—(SO₂)R⁸, —COR⁸ and —C(O)NH—R⁴, R⁸ is selected from optionallysubstituted lower alkyl, optionally substituted aryl and optionallysubstituted heteroaryl or R⁶ and R⁷ together with the nitrogen to whichthey are attached form a heteroaryl.
 15. The method of claim 14 whereint is
 0. 16. A method for treating a disease, condition, or disorderwhich responds to the inhibition of potassium channel function byadministering to a patient in need thereof, a pharmaceutically effectiveamount of a compound having the following formula or a pharmaceuticallyacceptable salt, ester, amide, or stereoisomer thereof:

wherein, v is 1; t is 0, 1, or 2; X, in an orientation R¹—X—, isselected from —(CR⁴ ₂)_(p)—; —(CR⁴ ₂)_(m)O(CR⁴ ₂)_(n)—; —(CR⁴₂)_(m)CH═CH(CR⁴ ₂)_(s)—; —(CR⁴ ₂)_(m)CH≡CH(CR⁴ ₂)_(s)—; and —(CR⁴₂)_(m)—A—(CR⁴ ₂)_(m)—; where p is an integer of 0 to 5, n is an integerof 2 to 4, m is an integer of 0 to 4 and s is an integer of 1 to 4; A isan optionally substituted 3 to 7 membered carbocyclic ring; each R⁴ isindependently selected from H, a lower alkyl, an aryl and a heteroaryl;R¹ is selected from an optionally substituted aryl and an optionallysubstituted heteroaryl; Y, in an orientation R²—Y—, is selected from—(CR⁴ ₂)_(q)—; —(CR⁴ ₂)_(m)O(CR⁴ ₂)_(n)—; —(CR⁴ ₂)_(m)CH═CH(CR⁴ ₂)_(m)—;—(CR⁴ ₂)_(m)CH≡CH(CR⁴ ₂)_(m)—; —(CR⁴ ₂)_(m)—A—(CR⁴ ₂)_(m)— and acycloalkyl, where q is an integer of 0 to 4 and m and n are as definedabove; R² is selected from H, an optionally substituted aryl and anoptionally substituted heteroaryl; and R³ is selected from H, optionallysubstituted lower alkyl, optionally substituted aryl, optionallysubstituted heteroaryl and —NR⁶R⁷, where R⁶ is selected from H andoptionally substituted lower alkyl; R⁷ is H, optionally substitutedlower alkyl, optionally substituted aryl, —(SO₂)R⁸, —COR⁸ and—C(O)NH—R⁴, R⁸ is selected from optionally substituted lower alkyl,optionally substituted aryl and optionally substituted heteroaryl or R⁶and R⁷ together with the nitrogen to which they are attached form aheteroaryl.
 17. The method of claim 16 wherein t is
 0. 18. A method fortreating a disease, condition, or disorder which responds to theinhibition of potassium channel function by administering to a patientin need thereof, a pharmaceutically effective amount of a compoundhaving the following formula or a pharmaceutically acceptable salt,ester, amide, or stereoisomer thereof:

wherein, v is 1; t is 0, 1, or 2; X, in an orientation R¹—X—, isselected from —(CR⁴ ₂)_(p)—; —(CR⁴ ₂)_(m)CH═CH(CR⁴ ₂)_(s)—; —(CR⁴₂)_(m)CH≡CH(CR⁴ ₂)_(s)—; and —(CR⁴ ₂)_(m)—A—(CR⁴ ₂)_(m)—; where p is aninteger of 0 to 5, m is an integer of 0 to 4 and s is an integer of 1 to3; A is an optionally substituted 3 to 7 membered carbocyclic ring; eachR⁴ is independently selected from H, a lower alkyl, an aryl and aheteroaryl; R¹ is selected from an optionally substituted aryl and anoptionally substituted heteroaryl; R² is an optionally substitutedphenyl; and R³ is selected from H, optionally substituted lower alkyl,optionally substituted aryl, optionally substituted heteroaryl and—NR⁶R⁷, where R⁶ is selected from H and optionally substituted loweralkyl; R⁷ is H, optionally substituted lower alkyl, optionallysubstituted aryl, —(SO₂)R⁸, —COR⁸ and —C(O)NH—R⁴, R⁸ is selected fromoptionally substituted lower alkyl, optionally substituted aryl andoptionally substituted heteroaryl or R⁶ and R⁷ together with thenitrogen to which they are attached form a heteroaryl.
 19. The method ofclaim 18 wherein t is 0.